Efficacy of DZ1462, a Novel Sodium-phosphate Transporter Inhibitor, on 5/6 Nephrectomy-induced Hyperphosphatemia Model Rats

doi:10.12300/j.issn.1674-5817.2021.138

Abstract

Abstract:

Objective To study the efficacy of DZ1462, a novel sodium-phosphate transporter inhibitor, on rat hyperphosphatemia models established by 5/6 nephrectomy.Methods Totally 156 rats were randomly selected into four groups. Rats fed a normal diet were control group, named as group Ⅰ (n=6); rats fed a normal diet after 5/6 nephrectomy were named as group Ⅱ (n=60); rats fed a high phosphate diet after 5/6 nephrectomy were named as group Ⅲ (n=60); rats fed a high phosphate diet after sham surgery were named as group Ⅳ (n=30). The molding cycle was 10 weeks. Serum Pi was detected and the number of animal deaths was recorded every two weeks. Hematoxylin-eosin (HE) staining was performed to observe the change in kidney pathology, and to screen animal models with high phosphorus blood syndrome. Totally 18 model rats that met the inclusion criteria (all of group Ⅲ) were selected and randomly assigned to three groups: the model control group recorded as the G2 group; the DZ1462 administration group (30 mg/kg, tid, 21 d) recorded as the G3 group; the Sevelamer administration group (250 mg/kg, tid, 21 d) recorded as the G4 group. In addition, the normal control group was set as the G1 group. Serum phosphate levels were measured using a kit.Results In the 8^th and 10^th weeks, compared to group Ⅰ, serum phosphorus in group Ⅲ showed a significant difference (P < 0.01). The kidneys in group Ⅲ had obvious glomerular sclerosis, renal tubular atrophy, degeneration, interstitial inflammation, fibrosis, and calcification. Similarly to chronic kidney disease accompanied by hyperphosphatemia, the animal model was established successfully. At each time point, the serum phosphorus inhibition rate of the G3 group was significantly higher than that of the G4 group (P < 0.05).Conclusion DZ1462, as a novel small-molecule inhibitor of intestinal sodium and phosphorus transporter, can effectively inhibit intestinal phosphorus ion absorption in rat hyperphosphatemia model, and is expected to become a potential drug for the clinical treatment of hyperphosphatemia.

Key words: 5/6 Nephrectomy, Hyperphosphatemia, Sodium-phosphate transporter inhibitors, DZ1462, Rats

CLC Number:

Q95-33

Xiao LU, Lin ZHANG, Hui JI, Shanxiang JIANG. Efficacy of DZ1462, a Novel Sodium-phosphate Transporter Inhibitor, on 5/6 Nephrectomy-induced Hyperphosphatemia Model Rats[J]. Laboratory Animal and Comparative Medicine, 2022, 42(3): 187-193.

Figures/Tables 5

Table 1 Mortality of different group rats within 10 weeks after modeling

分组 Group	动物数量 Animal n	第1周 1^st Week		第3周 3^rd Week		第5周 5^th Week		第7周 7^th Week		第10周 10^th Week
分组 Group	动物数量 Animal n	No.	Rd%	No.	Rd%	No.	Rd%	No.	Rd%	No.	Rd%
Ⅰ	6	0	0	0	0	0	0	0	0	0	0
Ⅱ	60	6	10	3	15	0	15	6	25	5	30
Ⅲ	60	8	13	2	16	2	20	2	23	10	40
Ⅳ	30	0	0	1	3	1	6	0	6	0	6

Figure1 Serum phosphorus levels in different groups of ratsNote： GⅠ， normal rats with a normal diet （groupⅠ）；GⅡ， 5/6 nephrectomy rats with a normal diet （group Ⅱ）；GⅢ， 5/6 nephrectomy rats with a high Pi diet （group Ⅲ）；GⅣ， sham surgery rats with a high Pi diet （group Ⅳ）. **Represent serum Pi has a highly significant difference between Group Ⅰ and Group Ⅲ at the 8th and 10th week （P < 0.01）.

Figure 2 Pathological evaluation of kidney tissue in 5/6 nephrectomy model rats （HE staining）Note： GⅠ is normal rats with a normal diet （groupⅠ）， GⅢ is 5/6 nephrectomy rats with a high Pi diet （groupⅢ）. The magnification of the upper and the lower is 100 and 200， respectively. The solid arrow shows the interstitial fibrosis and inflammatory， and the dashed arrow shows glomerular sclerosis.

Figure 3 Comparison of serum phosphorus levels among different groups of rats after drug treatmentNote： G1 is normal rats with a normal diet； G2 is 5/6 nephrectomy and high diet model rats received a normal diet； G3 is 5/6 nephrectomy and high diet model rats received a high Pi diet and DZ1462 30 mg/kg； G4 is 5/6 nephrectomy and high diet model rats received a high Pi diet and Sevelamer 250 mg/kg. **Represent serum Pi in G2 is significantly higher than that in G1 on days 0， 7， 14， and 21 （P < 0.01）.

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